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Turner's syndrome and pregnancy: Has the 45,X/47,XXX mosaicism a different prognosis? Own clinical experience and literature review
Abstract
Turner's syndrome is characterized by an ovarian failure which occurs in most cases before puberty and leads to infertility. In less than 10% of women with Turner syndrome, puberty may occur and spontaneous pregnancies is possible but with a high risk of fetal loss, chromosomal and congenital abnormalities. We present the case of a 33-year-old woman with a mosaic Turner's syndrome karyotype 45,X/47,XXX who conceived spontaneously and had two successful pregnancies. Short stature was the only manifestation of Turner's syndrome. In the present report, we reviewed the available literature on the fertility of women with Turner's syndrome and the phenotypic effects of mosaicism for a 47,XXX cell line in Turner's syndrome.
... Short stature may be the only manifestation of a 45, X cell line. Ovarian function in women with the 45,X/47, XXX karyotype ranges from normal to virtually absent with normal ovarian anatomy to streak ovaries, likely depending on the tissue distribution of the two cell lines [52,53]. Follicle number may be low with its attendant premature ovarian insufficiency, but spontaneous (natural) pregnancy is more common than the very low rate in those with 45, X karyotype [52]. ...
... Ovarian function in women with the 45,X/47, XXX karyotype ranges from normal to virtually absent with normal ovarian anatomy to streak ovaries, likely depending on the tissue distribution of the two cell lines [52,53]. Follicle number may be low with its attendant premature ovarian insufficiency, but spontaneous (natural) pregnancy is more common than the very low rate in those with 45, X karyotype [52]. There are multiple case reports, many with "a review of the literature" as part of the title. ...
... One might summarize that those with the 45,X/47,XXX mosaic karyotype in general have a mild Turner syndrome phenotype, most, but not all, with short stature, spontaneous pubertal maturation and menarche without structural abnormalities. Spontaneous pregnancies are far more common in these women than in those with other karyotypes; however, one must consider publication bias making it likely that the actual pregnancy rate is lower than commonly considered [52,54]. The women are however prone to premature ovarian insufficiency, often by age 30 y. ...
The overall incidence of sex chromosome aneuploidies is approximately 1 per 500 live-born infants, but far more common at conception. I shall review the fertility aspects of the sex chromosome trisomies, XXY, XYY, XXX, with special reference to the karyotype 45,X/47,XXX. Each has a "specific" (but variable) phenotype, but may be modified by mosaicism. Although the alterations in the hypothalamic-pituitary-gonadal axis are important (and discussed), the emphasis is on potential fertility. The reproductive axis is often affected in females with the 47,XXX karyotype with diminished ovarian reserve and accelerated loss of ovarian function. Fewer than 5 % of females with the Turner syndrome have the 45,X/47,XXX karyotype. They have taller stature and less severe fertility issues compared to females with the 45,X or other forms of Turner syndrome mosaicism. For the 47,XXY karyotype non-obstructive azoospermia is almost universal with sperm retrieval by micro-testicular sperm extraction possible in slightly fewer than half of the men. Men with the 47,XYY karyotype have normal to large testes and much less testicular dysfunction than those with the 47,XXY karyotype. They do have a slight increase in infertility compared to the reference population, but not nearly so severe as those with 47,XXY karyotype. Assisted reproductive technology, especially micro-TESE has an important role, especially for those with 47,XXY; however, more recent data show promising techniques for the in vitro maturation of spermatogonial stem cells and 3-D organoids in culture. Assisted reproductive technology is more complex for the female, but vitrification of oocytes has shown promising advances.
... The main cause of gonadal dysgenesis in TS cases is haploinsufficiency of the X-chromosome genes that leads to premature ovarian senescence [7]. The presence of dysgenetic gonad is more pronounced in classical cases (45,X) where the X chromosome is completely destroyed. ...
... Although there are isolated case series and reviews of spontaneous and IVF pregnancies in classical and mosaic TS cases [9], there are no publications using homologous intracytoplasmic sperm injection cycle in large patient series. Previous studies in the management of infertility due to TS mostly reported results of oocyte donation [7,9]. On the contrary, our study will allow obtaining new data by applying homologous intracytoplasmic sperm injection to all TS cases. ...
... However, in later studies, healthy and term pregnancies have been reported in cases with other mosaic karyotype forms. In accordance with this Bouchlariotou et al. [7] reported that 33-year-old woman with a mosaic Turner's syndrome karyotype 45,X/47,XXX who conceived spontaneously and had two successful pregnancies. Likewise, in our study, 12 of 32 cases with 45,X/46,XX/47,XXX karyotypes became pregnant and 7 of them resulted in healthy and term delivery. ...
Background: Although pregnancy is reported in both classical and mosaic forms of Turner syndrome (TS), both spontaneous and in-vitro-fertilisation (IVF) success rates were found higher in mosaic cases. In this study we analysed homologous intracytoplasmic sperm injection cycle results of infertile patients diagnosed with mosaic TS. Methods: Ninety nine female patients who had infertility complaints for 2 years or more and were diagnosed with mosaic TS were included in the study. They were treated according to a standard antagonist protocol. Embryo transfer was performed after pre-implantation genetic diagnosis (PGD) in 53 cases while embryo transfer was performed in remaining 46 cases without PGD. Results: While 45,X/46,XX karyotype was found in 55 of 99 cases, 45,X/46,XX/47,XXX karyotype was found in 32 cases. The remaining participants consisted of rare karyotype forms. The total number of patients conceived after the antagonist protocol was 31 (31.3%). While 18 of these cases resulted in term delivery (58%), the remaining 13 cases resulted in miscarriage (41.9%). Pregnancy could not be obtained in only 2 cases whose karyotype were 45,X/47,XXX and 45,X/46,XX/46,XY. Karyotype analysis was performed in only 2 of 18 newborn babies due to suspicious physical findings, but the results were reported as normal. Discussion: On the basis of our observations in this largest mosaic TS series, homologous IVF should be considered in infertile patients with Turner syndrome with high-grade mosaicism. PGD should also be recommended to TS patients on IVF treatment.
... In order to exclude the presence of a Y-cell line but also to properly inform the girl about her fertility chances, a FISH analysis was performed on buccal cells following the standard protocols [15]. Surprisingly, a 47, XXX [78] / 45, X [33] / 46, XX [7] karyotype was reported for these cells. This additional FISH examination showed that this was not a full-blown monosomy case but a patient with hidden mosaicism. ...
... Especially since the freezing and thawing of ovarian tissue will also have a negative effect on the number of viable oocytes and thus the chance of pregnancy and live birth. In addition, patients with TS are known to have a higher risk of having a miscarriage [20]) and a slightly higher risk of having a child with a congenital disorder [20,33]. Therefore, not only the quantity but also the functionality of the oocytes and supporting ovarian cells must be considered. ...
In this case report, we highlight the practical dilemma, i.e. to perform ovarian tissue cryopreservation surgery in a 45, X Turner Syndrome patient or not, by reporting on the presence of follicles in a 13-year-old female diagnosed with 45, X monosomy and an unmeasurable anti-müllerian hormone serum level. We compare our results with previous research, highlight the challenges we faced in this case and provide recommendations for daily practice. Hereby, we demonstrate that excluding certain subgroups of Turner Syndrome patients (e.g. monosomy patients, and/or girls with an anti-müllerian hormone level below 2.0 ng/l) may be premature, especially based on the current state of published research data. This practical example of a challenging dilemma in the counselling of Turner Syndrome patients for fertility preservation is of interest for clinicians involved in fertility counselling and Turner Syndrome care.
... Turnerjev sindrom (45, X), Klinefelterjev sindrom (47, XXY) ter XYY sindrom so najpogostejše anevploidije spolnih kromosomov, ki so tesno povezane z izgubo reproduktivne sposobnosti, sterilnostjo ter zaostankom razvoja govora (9). Povezujejo jih tudi z drugimi razvojnimi, telesnimi, kognitivnimi, socialnimi ter verbalnimi odmiki (10,11). ...
Kvantitativna fluorescentna verižna reakcija s polimerazo (QF-PCR) je uveljavljena metoda za usmerjeno, hitro, zanesljivo in poceni določanje najpomembnejših kromosomskih anomalij v prenatalni diagnostiki. To so trisomije kromosomov 13, 18 in 21, ki jih v Laboratoriju za medicinsko genetiko UKC Maribor rutinsko določamo od leta 2008 z lastno razvitim testom. Določanje številčnih sprememb kromosomov X in Y je del QF-PCR testa, ko se ta izvaja kot samostojni test. Trenutno veljavne smernice britanskega združenja za klinično citogenetiko priporočajo usmerjeno diagnostiko oz. preiskovanje prenatalnih vzorcev z metodo QF-PCR ob utemeljenem sumu na številčne anomalije spolnih kromosomov. V prispevku predstavljamo metodologijo in verifikacijo določanja številčnih anomalij kromosomov X in Y z uporabo mikrosatelitnih genetskih označevalcev z metodo QF-PCR. Gre za razširitev zmožnosti QF-PCR analize lastnega razvoja, ki vključuje pripravo optimiziranih kombinacij dodatnih devet začetnih oligonukleotidov, specifičnih za kromosoma X in/ali Y za izvajanje hkratne verižne reakcije s polimerazo. Za verifikacijo smo uporabili 23 predhodno citogenetsko opredeljenih vzorcev s prisotnimi različnimi oblikami odstopanj v številu kromosomov X in Y. Predstavljeni so tudi rezultati verifikacije metode, ki je pokazala 100% ujemanje rezultatov.
... The incidence of sex chromosome abnormalities is approximately 1/300-1/400 [1]. Clinical manifestations are diverse, with some patients having no abnormal phenotype, and others showing height abnormalities, organ structural abnormalities, intellectual disability, neurological dysfunction, and infertility caused by dysplasia of secondary sexual characteristics [2,3]. ...
Background
Early and intermediate serological screening cannot detect sex chromosome abnormalities. Currently, noninvasive prenatal testing (NIPT) is the only procedure available for screening such disorders; however, its use is controversial.
Methods and Results
A total of 47,855 pregnant women underwent NIPT at our referral center from January 2014 to December 2020. Of the 314 patients with a positive NIPT indicating sex chromosome abnormalities, 260 were screened via karyotype analysis and single nucleotide polymorphism (SNP) array after amniotic fluid extraction; 96 cases were confirmed. Karyotype analysis and SNP array were consistent in the diagnosis of 88 out of the 96 fetuses. The positive predictive value (PPV) for sex chromosome abnormalities was found to be 36.9%. The PPV in patients aged 30–34 years was significantly higher than that in patients aged < 30 years. No statistically significant difference was observed on the PPV among patients with or without previous adverse pregnancy outcomes. Moreover, 83 women carrying fetuses were diagnosed with a sex chromosome abnormality terminated their pregnancy.
Conclusions
Improvements in detection and analytical technologies are needed to increase the accuracy of sex chromosome abnormalities detection. Pregnant women with a positive NIPT for these abnormalities may require invasive diagnostic procedures such as karyotype analysis and SNP array for better genetic counseling.
... When compared to the classical form, mosaic karyotype TS cases are more likely to present spontaneous puberty, normal levels of serum sex steroids and gonadotropins and follicles in ovarian biopsies (Borgström, 2009). In addition, the chance of spontaneous conceiving in women with TS was reported only 2-10%, most of which are the cases of mosaic pattern and those with 45,X monosomy are candidates for oocyte donation (Hovatta, 2012;Sybert, 2002;Bouchlariotou, 2011). ...
The aim of study is the prevalence and clinical presentation of Turners syndrome patients presenting with infertility. Patient were enrolled having complaints of menstrual problems and infertility, recruited from the Department of Obstetrics and Gynecology, Sir Sunderlal Hospital, Institute of Medical Sciences, Banaras Hindu University, Varanasi. Chromosomal analysis was performed on phytohaemagglutinin (PHA)-stimulated peripheral lymphocyte cultures using standard conventional cytogenetic methods. GTG-banding was performed on 253 patients in the Cytogenetics Laboratory. All the patients underwent a physical examination and were enquired about their medical history and reproductive problems. Hormonal evaluation and USG was done after their consent. The prevalence of 45,X mosaicism in hospital was 5.5% (14/253), and the mosaic karyotype of our study accounted for 71.42% (10/14) having Turner syndrome cases. This was as high as compared with the studies reported from Asia, Europe, South America, and other parts of the world. The affected patients showed genital abnormalities, menstrual problems and infertility. Infertility problem is increasing and the genetic factors including Turners and its mosaic are the vital factors causing decrease in ovarian reserve and Infertility. Extensive cytogenetic assessment may improve the finding rate in patients with congenital dysplasia, or a history of abnormal pregnancy or even infertility. Karyotyping plays a crucial role in prognosis and assisted reproduction or early surgical treatment.
Turner syndrome (TS) is caused by the total or partial loss of the second sex chromosome; it occurs in 1 every 2,500–3,000 live births. The clinical phenotype is highly variable and includes short stature and gonadal dysgenesis. In 1959, the chromosomal origin of the syndrome was recognized; patients had 45 chromosomes with a single X chromosome. TS presents numerical and structural abnormalities in the sex chromosomes, interestingly only 40% have a 45, X karyotype. The rest of the chromosomal abnormalities include mosaics, deletions of the short and long arms of the X chromosome, rings, and isochromosomes. Despite multiple studies to establish a relationship between the clinical characteristics and the different chromosomal variants in TS, a clear association cannot yet be established. Currently, different mechanisms involved in the phenotype have been explored. This review focuses to analyze the different chromosomal abnormalities and phenotypes in TS and discusses the possible mechanisms that lead to these abnormalities.
Objective
To assess the clinical performance of noninvasive prenatal screening (NIPS) for both common trisomy and sex chromosome aneuploidy (SCA).
Methods
We recruited 71,888 pregnant women to undergo NIPS testing from December 2015 to June 2021. Demographic characteristics, diagnostic results and follow-up outcomes were collected.
Results
There were a total of 381 high-risk cases for common trisomy and 343 positive screens for SCA. Invasive prenatal diagnosis (IPD) was performed in 507 (70.0%) participants. The positive predictive value (PPV) was 83.7% for T21, 72.5% for T18, 14.3% for T13, 31.9% for 45,X, 72.0% for 47,XXX, 89.8% for 47,XXY and 72.2% for 47,XYY, respectively. Logistic regression analysis presented a significant association between Z-score and PPV in common trisomy (P < 0.05) while not in SCA (P > 0.05). PPV in the high-risk group (Z-score ≥ cutoff) was superior to that in the intermediate risk group (3 ≤ Z-score < cutoff) for T21/T18/T13. PPV for 45,X, 47,XXY and 47,XYY tended to be higher with the increasing Z-score, except for 47,XXX.
Conclusions
NIPS would be a valuable strategy in prenatal screening, while cautions should be kept in mind for subsequent genetic consulting about the risk of Z-score.
Introduction
Sex chromosome aneuploidies (SCAs) result from errors during meiosis and are among the most common chromosome abnormalities observed in humans. Manifestations include low fertility, infertility, delayed language development, and dysfunction in motor development. Non-invasive prenatal screening (NIPS) based on cell-free fetal DNA from the peripheral blood of pregnant women is increasingly used for the screening of fetal chromosome abnormalities, including screening for fetal gender and fetal sex chromosome aneuploidy. A systematic review of the literature about NIPS for SCAs is needed.
Areas covered
This review evaluated a vast array of published studies focusing on the clinical significance, detection methods, performance of NIPS for SCAs, and the management of positive SCA results following screening with the aim of facilitating a comprehensive and systematic understanding of NIPS for SCAs.
Expert commentary
Looking forward, NIPS is expected to become the primary screening test for common aneuploidies as well as other chromosome abnormalities, including some micro-deletions and micro-duplications, with the potential to transition from a screening test to a prenatal diagnosis method. Ultimately, the goal is to provide a safe and accurate method for increasing early diagnosis to improve long-term outcomes for the SCA patients and families by well- informed health care providers.
A total of 20 clinical pregnancies was achieved among 18 women with Turner's syndrome who were treated in an oocyte donation
programme. The oocytes were donated by voluntary unpaid donors. A mean of 1.8 embryos per transfer was given to each recipient
by way of 28 fresh and 25 frozen embryo transfers. With fresh and frozen embryos, 13 and seven pregnancies respectively were
achieved. The clinical pregnancy rate per fresh embryo transfer was 46%, and the implantation rate 30%, being similar to the
corresponding rates among our oocyte recipients with primary ovarian failure in general. The corresponding rates with frozen
embryos were 28 and 19%. Of these pregnancies, 40% ended in miscarriage. This high rate may be explained by uterine factors.
Six women were hypertensive during pregnancy, a rate comparable with that in other oocyte donation pregnancies. All these
women delivered by Caesarean section. Pregnancy and implantation rates after oocyte donation were high in women with Turner's
syndrome, but the risk of cardiovascular and other complications is high. Careful assessment before and during follow-up of
pregnancy are important. Transfer of only one embryo at a time to avoid the additional complications caused by twin pregnancy
is recommended.
In this report, we present the cytogenetic findings in 478 patients with Turner syndrome diagnosed in Leuven in the period 1965-1989. The karyotypic anomalies are classified into seven groups: 1) classic, 45,X karyotype (52.1%); 2) mosaic 45,X/46,XX (10.9%); 3) mosaic 45,X/47,XXX and other "super-female" cell lines (4.6%); 4) isochromosomes i(Xq) and i(Xp) (16.1%); 5) ring chromosomes r(X) (4.4%); 6) other structural aberrations of the X chromosome (7.7%); and finally 7) mosaic 45,X/46,XY patients (4%). The most pertinent chromosomal findings are briefly discussed and compared with previous reported surveys on subject.
A spontaneous abortion (miscarriage) is the natural termination of pregnancy before the fetus is capable of extrauterine life (Scott, 1986). Spontaneous abortions can be divided into two groups: early abortions, up to 12 weeks of age, and late abortions 13–18 weeks of age (Ornoy et al., 1981). There are different terms for fetuses who die later in pregnancy. Early still-birth is considered to be between the 20ieth and 24th week of pregnancy. Stillborn infants are all infants who die from the 25th week of pregnancy onwards.
One of the characteristic symptoms in girls and women with Turner syndrome (TS) is ovarian failure with infertility. Puberty starts spontaneously in 15% to 30% of girls with this syndrome but less than 5% reach menarche with the possibility of becoming pregnant because ovarian follicles secreting estrogen disappear prematurely. In a prior study, the investigators cryopreserved biopsy specimens from ovarian cortical tissue of adolescent girls with TS and found remaining follicles in 8 of 10 girls. This study investigated clinical and laboratory parameters that could help identify which girls with TS are likely to benefit from freezing of ovarian tissue to preserve fertility. The study subjects were 57 girls with TS, aged 8 to 19.8 years who had been referred to a fertility unit by 25 pediatric endocrinologists in Sweden. Ovarian cortical tissue was biopsied laparoscopically for follicle counts and cryopreserved. Parameters analyzed included karyotype, age at biopsy, spontaneous onset of puberty and menarche, number of follicles, and serum concentrations of follicle stimulating hormone, luteinizing hormone, and anti-Müllerian hormone. Among the 57 girls in the study, ovarian biopsy was feasible in 47, and follicles were identified in 15 (26%). Follicles were found in 6 of 7 (86%) girls with mosaicism, in 6 of 22 (27%) with structural chromosomal abnormalities, and in 3 of 28 (10.7%) with karyotype 45X. Signs of spontaneous onset of puberty were found in 19 girls, 11 of whom (58%) had follicles in the tissue. Menarche had been reached spontaneously in 13 girls; of these, 8 (62%) had follicles. Despite a high-negative predictive value for finding follicles in girls below 12 years, age was not a significant factor. These findings show that girls with TS who have the highest likelihood of having remaining follicles are those with mosaicism, spontaneous onset of puberty, and normal hormone concentrations.
Turner’s syndrome associated with an X ring chromosome, r (X), is rare and there has been no report on pregnancy in Turner’s syndrome with 45, X/46, Xr (X)/46, XX mosaicism. A patient with this karyotype who lacked the clinical manifestation of characteristic phenotype of Turner’s syndrome except for short stature had two pregnancies. This is the first case of successful pregnancy in patient with X, Xr(X), XX mosaic Turner’s syndrome.
Ovarian failure can result from several different genetic mechanisms—X chromosomal abnormalities, autosomal recessive genes causing various types of XX gonadal dysgenesis, and autosomal dominant genes. The number and precise location of loci on the X are still under investigation, but it is clear that, in aggregate, these genes are responsible for ovarian maintenance, given that monosomy X shows germ cells that undergo accelerated atresia. Despite recent hypotheses, at present there is no evidence for a gene directing primary ovarian differentiation; this process may be constitutive. Phenotypic/karyotypic correlation and limited molecular confirmation have long shown that proximal Xp and proximal Xq contain regions of the most importance to ovarian maintenance. Terminal deletions at Xp11 result in 50% primary amenorrhea and 50% premature ovarian failure or fertility. Deletions at Xq13 usually produce primary amenorrhea. Terminal deletions nearer the telomeres on either Xp of Xq bring about premature ovarian failure more often than complete ovarian failure. The X-linked zinc finger gene (ZFX) and diaphanous 2 Drosophila homologue (DIAPH2) are the only candidate genes for ovarian maintenance that map to the X chromosome. Additional, as yet unidentified, genes along the X chromosome must be involved. The search for these genes in humans is hampered by the lack of candidate genes that map to the X chromosome, the scarcity of patients with fortuitous autosomal translocations, and small pedigrees, which hinder mapping of the loci. In addition, difficulties with human germ cell research also make it challenging to dissect genes important to ovarian development. Autosomal genes also are involved in ovarian differentiation and gonadal failure. Follicle-stimulating hormone receptor and ataxia telangiectasia are examples of autosomal genes known to cause human ovarian failure. Transgenic mouse models point to many other candidate autosomal genes, and sequencing of the human homologues in affected women should lead to the discovery of new genes responsible for human ovarian failure. Identification, functional analysis, and mapping of novel genes specifically expressed in the ovary of mice and women eventually should lead to fruitful dissection of essential genes in mammalian ovarian development and maintenance. Am. J. Med. Genet. (Semin. Med. Genet.) 89:186–200, 1999. © 2000 Wiley-Liss, Inc.
Very little is known about the adult adaptation of individuals with sex chromosome abnormalities (SCA) except for a few reports based upon biased samples of clinically identified patients. This first report from the Denver SCA study on the adult psychosocial adaptation of 36 unselected propositi, identified at birth, shows a continuation of mild psychological and social problems. Psychiatric interviews and self-reported information revealed that adaptation is quite variable, with many of the nonmosaic propositi not faring as well as their siblings, but in a few instances exceeding the success of brothers and sisters. Within this group of SCA subjects a subset demonstrated more marked pathology and a tendency to overrate their social adaptation relative to the psychiatric interviewer, suggesting that the exclusive use of self-report questionnaires may not provide accurate assessment of psychological characteristics in this and other special populations. The full adult SCA behavioral phenotype has not yet been established but is emerging through additional reports from this and other studies of unselected SCA adults. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:200–206, 1999. © 1999 Wiley-Liss, Inc.